Coupling of aryl halides with aryl boronic acids with P(C6H5)(2-C6H4Cl)2 as the supporting ligand

Article abstract of DOI:10.1021/om020885i

The chlorinated triarylphosphine P(C₆H₅)(2-C₆H₄Cl)₂ (1) has been used as a supporting ligand in the Suzuki-Miyaura coupling of aryl boronic acids with aryl halides. Aryl bromides without ortho substituents were successfully coupled at room temperature, while reactions involving sterically hindered aryl bromides required slight heating (70°C). Electron-deficient aryl chlorides were also successfully coupled with heating (90°C). Key reaction parameters such as order of addition, choice of mineral base, solvent volume, temperature, 1/Pd ratio, as well as electronic and steric variation of the aryl halide have been investigated and are reported.

Full text of DOI:10.1021/om020885i

Organometallics 2003, 22, 523-528
523
Cou p lin g of Ar yl Ha lid es w ith Ar yl Bor on ic Acid s w ith
P (C6H5)(2-C6H4Cl)2 a s th e Su p p or tin g Liga n d
Michelle R. Pramick, Sara M. Rosemeier, Maryann T. Beranek,
Stephanie B. Nickse, J oshua J . Stone, Robert A. Stockland, J r.,*
Steven M. Baldwin, and Margaret E. Kastner
Department of Chemistry, Bucknell University, Lewisburg, Pennsylvania 17837
Received October 23, 2002
The chlorinated triarylphosphine P(C6H5)(2-C6H4Cl)2 (1) has been used as a supporting
ligand in the Suzuki-Miyaura coupling of aryl boronic acids with aryl halides. Aryl bromides
without ortho substituents were successfully coupled at room temperature, while reactions
involving sterically hindered aryl bromides required slight heating (70 °C). Electron-deficient
aryl chlorides were also successfully coupled with heating (90 °C). Key reaction parameters
such as order of addition, choice of mineral base, solvent volume, temperature, 1/Pd ratio,
as well as electronic and steric variation of the aryl halide have been investigated and are
reported.
The coupling of aryl boronic acids with aryl halides
(Suzuki-Miyaura reaction) has become one of the most
widely used methods for preparation of biaryls due to a
wide range of functional group tolerance and straight-
forward separation of products (eq 1).1 These reactions
F igu r e 1. Functionalized phosphine ligands used in
coupling reactions.
of aryl bromides and chlorides with aryl boronic acids.6
Bei reported that a P∩O compound (Figure 1) is also an
effective ligand for this reaction.7 Additionally, few
examples are known where triarylphosphines were used
in Suzuki-Miyaura couplings employing aryl chlorides.8
To determine if the simple addition of a halogen at the
ortho position of two of the phenyl rings of PPh3 could
lead to a active catalyst, we have investigated Suzuki-
Miyaura coupling reactions mediated by P(C6H5)(2-
C6H4Cl)2/Pd2(dba)3.
are typically carried out with phosphine-based pal-
ladium catalysts at elevated temperatures and aryl
bromides and iodides as substrates.2 Despite the intense
amount of attention this area has received, few systems
have been found that promote this reaction under mild
conditions.3 Aryl chlorides are attractive substrates for
this reaction; however, only a small number of success-
ful catalysts have been found that promote these reac-
tions.4 Some of the more recent advances in this area
involve the use of electron-rich or functionalized phos-
phine ligands (Figure 1).5 Buchwald has shown that
2-dicyclohexylphosphanyl-2′-dimethylaminobiphenyl is
an effective ligand for the room temperature coupling
The chlorinated triphenylphosphine, P(C6H5)(2-C6H4-
Cl)2 (1), was synthesized by treatment of 2-bromochlo-
robenzene with magnesium followed by addition of 0.5
equiv of PhPCl2 (eq 2; 57.5% isolated yield).9 Compound
* To whom correspondence should be addressed. Phone: 570-577-
1665. Fax: 570-577-1739. E-mail: rstockla@bucknell.edu.
(1) (a) Miyaura, N.; Yanagi, N.; Suzuki, A. Synth. Commun. 1981,
11, 513. (b) Miyaura, N.; Yamada, K.; Suginome, H.; Suzuki, A. J . Am.
Chem. Soc. 1985, 107, 972. (c) Suzuki, A. Pure Appl. Chem. 1991, 63,
419. (d) Suzuki, A. Pure Appl. Chem. 1994, 66, 213.
(2) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(3) (a) Campi, E. M.; J ackson, W. R.; Marcuccio, S. M.; Naeslund,
C. G. M. J . Chem. Soc., Chem. Commun. 1994, 2395. (b) Anderson, J .
C.; Namli, H.; Roberts, C. A. Tetrahedron 1997, 53, 15123. (c) J ohnson,
C. R.; J ohns, B. A. Synlett 1997, 1406. (d) Uozmi, Y.; Danjo, H.;
Hayashi, T. J . Org. Chem. 1999, 64, 3384. (e) Bussolari, J . C.; Rehborn,
D. C. Org. Lett. 1999, 1, 965. (f) Kataoka, N.; Shelby, Q.; Stambuli, J .
P.; Hartwig, J . F. J . Org. Chem. 2002, 67, 5553. The rates of coupling
reactions are dramatically increased with the use of TlOH as a base;
however, heath concerns limit widespread use. Frank, S. A.; Chen, H.;
Kunz, R. K.; Schnaderbeck, M. J .; Roush, W. R. Org. Lett. 2000, 2,
2691.
(4) (a) Zhang, C.; Huang, J .; Trudell, M. L.; Nolan, S. P. J . Org.
Chem. 1999, 64, 3804. (b) Grasa, G. A.; Hillier, A. C.; Nolan, S. P. Org.
Lett. 2001, 3, 1077.
(5) Littke, A. F.; Dai, C.; Fu, G. C. J . Am. Chem. Soc. 2000, 122,
4020.
1 was isolated as a colorless solid and was stable in air
for extended periods of time. The molecular structure
of 1 is shown in Figure 2 and crystallographic data and
(6) (a) Yin, J .; Buchwald, S. L. J . Am. Chem. Soc. 2000, 122, 12051.
(b) Wolfe, J . P.; Buchwald, S. L. Angew. Chem., Int. Ed. 1999, 38, 2413.
(c) Wolfe, J . P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J . Am.
Chem. Soc. 1999, 121, 9550.
(7) Bei, X.; Turner, H. W.; Weinberg, W. H.; Guram, A. S.; Petersen,
J . L. J . Org. Chem. 1999, 64, 6803.
(8) (a) Liu, S.-Y.; Choi, M. J .; Fu, G. C. Chem. Commun. 2001, 2408.
(b) Pickett, T. E.; Richards, C. J . Tetrahedron Lett. 2001, 42, 3767.
(9) Davis, M.; Mann. F. G. J . Chem. Soc. 1964, 3770.
10.1021/om020885i CCC: $25.00 © 2003 American Chemical Society
Publication on Web 01/01/2003

524 Organometallics, Vol. 22, No. 3, 2003
Pramick et al.
(1/Pd ) 2), THF (1 mL), and KF (3.3 equiv). Increasing
the 1/Pd ratio resulted in decreased yields of the biaryl
in room temperature reactions, but reactions carried out
at 70 °C were not significantly affected.11 Decreasing
the 1/Pd ratio to 1 did not adversely affect couplings
carried out at 70 °C, but room temperature reactions
were sluggish. Sterically hindered substrates were also
coupled by using this system, although high yields were
only obtained at 70 °C. The order in which 1 was added
to the reaction was a critical reaction parameter and
was investigated by using the coupling of 4-bromotolu-
ene with phenyl boronic acid as the test case. When 1
was added prior to the aryl bromide, yields of room
temperature couplings fell significantly (62% after 15
h). Similar reactions carried out at 70 °C were not as
dramatically affected (82% conversion). The amount of
solvent used in the reaction affected the reaction rate.
When 7 mL of THF was used for the coupling of
phenylboronic acid with bromobenzene, the coupling
reactions were sluggish (<25% conversion). Decreasing
the amount of solvent to 1 mL resulted in high yields
of the biaryl (>90%). With this amount of solvent, the
reactions are visibly heterogeneous; thus, the reactivity
of these systems may vary.
F igu r e 2. Molecular structure of 1 with thermal ellipsoids
at 50% probability. Selected bond distances (Å) and angles
(deg): P(1)-C(7) ) 1.835(3), P(1)-C(1) ) 1.840 (3), P(1)-
C(13) ) 1.834(3), C(13)-P(1)-C(7) ) 101.59(13), C(13)-
P(1)-C(1) ) 102.08(13), C(7)-P(1)-C(1) ) 101.04(13).
Ta ble 1. Cr ysta llogr a p h ic Da ta a n d Refin em en t
for Com p ou n d 1
The ability to use small amounts of catalyst and still
achieve high conversions is a great concern in cross-
coupling reactions due to the high cost of metals and
ligands. We have investigated various catalyst loadings
using the coupling of 4-bromoacetophenone with phenyl
boronic acid as a test case. As shown in Table 3, high
yields of the biaryl were obtained by using catalyst
loadings of as low as 0.01 mol % of Pd (0.005 mol % of
Pd2(dba)3). This corresponds to ∼10 000 turnovers.
Reactions with 0.001 mol % of Pd (0.0005 mol % of
Pd2(dba)3) afforded 4-phenylacetophenone in 70% yield
(70 °C, 1 h).
empirical formula
fw
C18H13Cl2P
331.15
298(2)
0.71073
monoclinic
P2(1)/c
9.3807(18)
9.9582(15)
18.028(4)
temp (K)
wavelength (Å)
cryst system
space group
a (Å)
b (Å)
c (Å)
R, γ (deg)
90
â (deg)
103.259(19)
1639.2(5)
4
1.342
0.483
vol (Å3)
Z
density (calcd) (Mg/m3)
abs coeff (mm-1
)
Self-coupling of the aryl boronic acid as well as aryl-
aryl exchange reactions between Pd-Ar and P-Ar are
typical side reactions encountered when triarylphos-
phine ligands are employed in coupling reactions.12
When 1 was employed as the supporting ligand, trace
amounts of 2-chlorobiphenyls were observed (<0.1% by
GC) as the result of aryl-aryl exchange followed by
coupling with an aryl boronic acid.13 The self-coupling
of the phenyl boronic acid was not significant when
reactions were carried out in the absence of oxygen. The
addition of small amounts of air (1 mL) resulted in
significant amounts of the self-coupling product. This
was consistent with the previous observation that air
accelerates this process.14
F(000)
680
cryst size (mm3)
0.65 × 0.44 × 0.30
2.23-27.50
-1 e h e 12,
-1 e k e 12,
-23 e l e 23
4956
3770 [R(int) ) 0.0286]
100.0
empirical
0.8771 and 0.7457
full-matrix least-squares on F2
θ range for data collection (deg)
index ranges
no. of reflns collected
no. of independent reflns
completeness to θ ) 27.50° (%)
abs correction
max and min transmission
refinement method
no. of data/restraints/parameters 3770/0/190
goodness-of-fit on F2
1.011
final R indices [I > 2σ(I)]
R indices (all data)
largest diff peak and hole
R1 ) 0.0570, wR2 ) 0.1230
R1 ) 0.1088, wR2 ) 0.1447
0.460 and -0.314 eÅ-3
The effect of different mineral bases on this reaction
was investigated by using the coupling of 4-bromotolu-
ene with phenyl boronic acid as a test case. Using KF‚
refinement parameters are listed in Table 1. The cone
angle of 1 (183°) is significantly larger than that of PPh3
(145°) due to the presence of the chlorine atoms in the
ortho positions.10
The results of coupling reactions employing aryl
bromides are summarized in Table 2. Reactions involv-
ing electron-deficient and electron-rich aryl bromides
were typically complete within 20 h at 25 °C or 1 h at
70 °C. The catalytic system investigated consisted of 1
equiv of aryl halide, 1.1 equiv of aryl-boronic acid,
Pd2(dba)3 (2, 1 mol % of Pd based upon aryl halide), 1
(11) The coupling of bromobenzene with phenyl boronic acid was
used as a test reaction for investigating the effect of variation of the
1/Pd ratio on the coupling reaction. When 1/Pd ) 4, 70% of the
bromobenzene was consumed (48 h, 25 °C). Reactions carried out at
70 °C afforded 90% conversion. Reducing the ratio (1/Pd ) 1) resulted
in 41% consumption of bromobenzene (48 h, 25 °C). Reactions carried
out at 70 °C afforded 84% conversion.
(12) (a) Kong, K. C.; Cheng, C. H. J . Am. Chem. Soc. 1991, 113,
6313. (b) Marcial, M. M.; Perez, M.; Pleixats, R. J . Org. Chem. 1996,
61, 2346.
(13) O’Keefe, D. F.; Dannock, M. C.; Marcuccio, S. M. Tetrahedron
Lett. 1992, 33, 6679.
(10) The cone angle of 1 was determined using the method of
Coville: Smith, J . M.; Coville, N. J . Organometallics 2001, 20, 1210.
(14) Moreno-Manas, M.; Perez, M.; Pleixats, R. J . Org. Chem. 1996,
61, 2346.

Coupling of Aryl Halides with Aryl Boronic Acids
Organometallics, Vol. 22, No. 3, 2003 525
Ta ble 2. Cou p lin g Rea ction s w ith Ar yl Br om id esa
Ta ble 4. Tr ea tm en t of 3 w ith Nitr ogen Don or s
gated how easily 1 was displaced from a discrete
palladium complex, PdCl2(P(C6H5)(2-C6H4Cl)2)2 (3).16
While no displacement of 1 was observed upon addition
of excess 2-bromopyridine, benzonitrile, 4-bromoben-
zonitrile, 4-chlorobenzonitrile, or 2-acetopyridine, the
addition of pyridine, 4-phenylpyridine, 4-methylpyri-
dine, 2,4-dimethylpyridine, and 4-methoxypyridine dis-
placed a significant amount of 1 from Pd (Table 4).17
These data suggested that a possible reason for the
reduced activity of 1/2 toward heteroaromatic systems
could stem from the formation of LnPd (L ) pyridine-
containing ligand) species.
While aryl bromides and aryl iodides are the typical
substrates used in Suzuki-Miyaura couplings, aryl
chlorides are attractive substrates. The results of the
coupling reactions involving aryl chlorides are sum-
marized in Table 5. While aryl bromides were coupled
by using a 1/Pd ratio of 2, reactions employing aryl
chlorides required slight heating and a 1/Pd ratio of 4
for high yields of the biaryl. Electron-deficient aryl
chlorides such as 4-chloroacetophenone and 4-chloro-
benzonitrile are effectively coupled with phenyl boronic
acid at 90 °C.18 This process was also tolerant of ortho
substituents as evidenced by the successful coupling of
o-tolyl boronic acid with 4-chloroacetophenone and
4-chlorobenzonitrile. The sluggish reactivity of 1/2
toward deactivated aryl chlorides was presumably due
to the weaker donor ability of 1 resulting in reduced
electron density on palladium.
a
Reactions were stirred at 25 °C for 20 h or 70 °C for 1 h with
1 equiv of aryl bromide, 1.1 equiv of aryl boronic acid, 3.3 equiv of
KF, Pd2(dba)3 (1 mol % Pd), 1 (2 mol %), and THF (1 mL). Yields
are based upon isolated material with the value in parentheses
referring to reactions at 70 °C; a ) heated for 2 h, b ) stirred for
30 h, c ) GC yield; d ) heated for 8 h.
Ta ble 3. In flu en ce of Low Ca ta lyst Loa d in g on th e
Cou p lin g Rea ction a
a
Reactions were heated to 70 °C for 1 h using 1 equiv of aryl
bromide, 1.1 equiv of aryl boronic acid, 3.3 equiv of KF, Pd2(dba)3,
1 (1/Pd ) 2), and THF (1 mL). Results are based upon isolated
material (average of two runs) unless specified. a ) GC yield.
While 1/2 was successful in catalyzing the coupling
reactions, the precise role of the chlorine substituent
in 1 was not known. The reduced basicity of the
phosphine due to the presence of the electron-withdraw-
ing chlorine atoms and the larger cone angle could
facilitate the formation of a coordinatively unsaturated
palladium species that would promote the initial oxida-
tive addition reaction. This process could be aided by
intramolecular coordination of one of the chlorines to
palladium. Such coordination of ortho-halogenated aryl
2H2O, K3PO4, Na2CO3, or NaOH as the base did not
significantly affect reactions carried out at 70 °C.
However, the yields of room temperature reactions were
lowered when Na2CO3 was used.
While a variety of substrates were coupled with the
catalyst system of 1/2, reactions employing aryl bro-
mides containing heteroatoms such as 2-bromopyridine
did not proceed to completion. It was possible that the
nitrogen donor of the reagent or product could displace
1 from palladium resulting in the formation of pyridine-
containing palladium compounds. Similar complexes
have been reported by Nolan to be much less active in
coupling reactions.15 To probe this further, we investi-
(16) We have recently reported that various monodentate phosphine
and bidentate nitrogen-containing ligands (2,2′-bipyridine, 4,4′-dinonyl-
2,2′-bipyridine, and 1,10-phenanthroline) readily displace 1 from 3:
Stone, J . J .; Stockland, R. A., J r.; Rath, N. P. Inorg. Chim. Acta. In
press.
(17) Using 20 equiv of 2,4-dimethyl pyridine or 4-phenylpyridine
(test cases) resulted in almost quantitative (>95%) displacement of 1
from palladium.
(18) There is no evidence for coupling of the chloride of the ligand
under the conditions used.
(15) Grasa, G. A.; Hillier, A. C.; Nolan, S. P. Org. Lett. 2001, 3, 1077.

526 Organometallics, Vol. 22, No. 3, 2003
Pramick et al.
Ta ble 5. Cou p lin g Rea ction s In volvin g Ar yl
Ch lor id esa
sodium and distilled under nitrogen. Diethyl ether and hexane
were dried by passage through a Grubbs-type solvent purifica-
tion system.22 Yields were determined based upon isolated
material and relative to the amount of starting aryl halide.
Elemental analyses were performed by Midwest Analytics.
NMR spectra were recorded on a Bruker Avance-300 MHz
spectrometer at 25 °C; chemical shifts are reported relative
to residual solvent resonances (1H and 13C). 31P NMR spectra
were referenced with external 85% H3PO4 (0 ppm). Quantita-
tive 31P NMR spectra were obtained with use of the inverse-
gated pulse program with a recycle delay of 30 s.
Syn th esis of P (C6H5)(2-C6H4Cl)2 (1).7 A round-bottom
flask was charged with Mg (1.48 g, 60.9 mmol) and an iodide
crystal. 2-Bromochlorobenzene (13.0 g, 68.0 mmol; dissolved
in ether (100 mL)) was added dropwise. The reaction proceeded
rapidly and was gently warmed to maintain reflux. Once all
the magnesium was consumed, PPhCl2 (5.37 g, 30.0 mmol;
dissolved in ether (20 mL)) was added dropwise with vigorous
stirring. After aqueous workup, 1 was separated from the
residue by distillation (220 °C) under vacuum (0.2 mmHg).
Compound 1 was recrystallized from ethanol and dried in
vacuo overnight affording 5.71 g (57.5%) of a colorless solid.
Anal. Calcd for C18H13Cl2P: C, 65.27; H, 3.93. Found: C, 64.97;
H, 4.00. 1H NMR (CDCl3, 25 °C): δ 6.89-7.5 (m 13H). 31P{1H}
NMR (CDCl3, 25 °C): -16.7 (s).
Molecu la r Str u ctu r e Deter m in a tion of 1. X-ray quality
crystals were grown by slow evaporation of a diethyl ether
solution containing 1. A suitable sample was selected, mounted,
and optically centered. Data collection was performed with a
Bruker P-4 diffractometer with Mo radiation KR (λ ) 0.71073
Å). 3770 independent reflections were collected over the range
of 2θ ) 2.50-55.00°. The positions and anisotropic thermal
parameters of the non-hydrogen atoms were refined on F2 with
use of direct methods with the SHELXTL97 package using 190
parameters yielding R ) 0.0570. The hydrogen atoms were
placed in calculated positions.
Gen er al P r ocedu r e for th e Cou plin g Reaction . Meth od
A (a r yl br om id es): A flask was charged in air with arylbo-
ronic acid, KF, Pd2(dba)3 (0.0029 g, 3.17 µmol), and the aryl
halide. The flask was evacuated and refilled with nitrogen,
and THF (0.5 mL) was added by syringe. After the mixture
was stirred for 10 min, 1 (0.0042 g, 12.6 µmol, dissolved in 0.5
mL of THF) was added by syringe. The reaction was stirred
at the desired temperature under nitrogen until GC analysis
revealed the consumption of the aryl halide. The reaction
mixture was diluted with 30 mL of ether and washed with
dilute NaOH (1 M), dilute HCl (1 M), and water. After drying
over MgSO4, the solvent was removed under vacuum and the
biaryl purified by column chromatography on silica. Meth od
B (a r yl ch lor id es): The same as method A with the exception
that 1 (0.0084 g, 25.4 µmol, 4 mol %) was added in the air
prior to evacuation and addition of the solvent (THF, 1.0 mL).
Syn th esis of Bip h en yl. Meth od A: The general procedure
was followed with bromobenzene (0.100 g, 0.64 mmol), phenyl
boronic acid (0.086 g, 0.71 mmol), and KF (0.12 g, 2.1 mmol).
After the mixture was stirred at 25 °C for 20 h, workup and
purification of the residue by column chromatography (silica
gel; hexane) afforded 0.090 g (91%) of biphenyl as a colorless
solid. Reactions carried out at 70 °C (1 h) afforded 0.093 g
(94%). The formation of biphenyl was confirmed by comparison
of the 1H and 13C NMR spectra of the purified material with
an authentic sample (Aldrich).
a
Reactions were heated to 90 °C for 30 h with 1 equiv of aryl
chloride, 1.1 equiv of aryl boronic acid, 3.3 equiv of KF, Pd2(dba)3
(1 mol % Pd), 1 (4 mol %), and THF (1 mL). Yields are based upon
isolated material (average of two runs) unless specified. a ) GC
yield.
groups is known.19 An additional possibility entails
intramolecular oxidative addition of the C6H4-Cl bond
across Pd to generate a four-membered palladacycle that
catalyzes the reaction.20
In summary, we have outlined a system for the
coupling of aryl bromides and chlorides with arylboronic
acids using a chlorinated triarylphosphine as the sup-
porting ligand. While the precise role of the chlorine
substituent of 1 is not known, this work demonstrates
that halogenated phosphine compounds can be success-
fully used as supporting ligands in the palladium-
mediated coupling of aryl boronic acids with aryl
halides. Furthermore, the ease in which 1 is displaced
from palladium suggests that 1 may be an attractive
alternative to PPh3 in reactions where loss of a phos-
phine is a critical step. Work is currently underway to
determine the effectiveness of 1 as well as other
chlorinated phosphine ligands such as PCy2(2-C6H4Cl)
in metal-catalyzed transformations.
Exp er im en ta l Section
Gen er a l Con sid er a tion s. All experiments were carried out
under an atmosphere of nitrogen with a Schlenk line or
glovebox. The boronic acids, KF, and phenyldichlorophosphine
were purchased from Aldrich and used as received. The aryl
halides were dried and purified prior to use. Pd2(dba)3 was
prepared as described in the literature.21 THF was dried over
Syn th esis of 2-m eth ylbip h en yl. Meth od A: The general
procedure was followed with 2-bromotoluene (0.11 g, 0.64
mmol), phenylboronic acid (0.086 g, 0.71 mmol), and KF (0.12
g, 2.1 mmol). After the mixture was stirred at 25 °C for 30 h,
(19) (a) Lahuerta, P.; Martinez, R.; Sanz, F.; Cantarero, A.; Torrens,
F. J . Chem. Res. 1988, 22, 261. (b) Estevan, F.; Garcia-Bemabe, A.;
Garcia-Granda, S.; Lahuerta, P.; Moreno, E.; Perez-Prieto, J .; Sanau,
M.; Ubeda, M. A. J . Chem. Soc., Dalton Trans. 1999, 3493. (c) Burk,
M. J .; Crabtree, R. H.; Holt, E. M. J . Organomet. Chem. 1988, 341,
495.
(21) Hegedus, L. Palladium in Organic Synthesis. In Organometal-
lics in Synthesis; Schlosser, M., Ed.; Wiley and & Sons: Chichester,
England, 1994; p 448.
(20) Dupont, J .; Pfeffer, M.; Spencer, J . Eur. J . Inorg. Chem. 2001,
1917.
(22) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.;
Timmers, F. J . Organometallics 1996, 15, 1518.

Coupling of Aryl Halides with Aryl Boronic Acids
Organometallics, Vol. 22, No. 3, 2003 527
workup and purification of the residue by column chromatog-
raphy (silica gel; hexane) afforded 0.093 g (86%) of 2-methyl-
biphenyl. Reactions carried out at 70 °C (2 h) yielded 0.102 g
(94%). The formation of 2-methylbiphenyl was confirmed by
1H and 13C NMR spectroscopy.7
Syn th esis of 4-Meth ylbip h en yl. Meth od A: The general
procedure was followed with 4-bromotoluene (0.11 g, 0.64
mmol), phenylboronic acid (0.086 g, 0.71 mmol), and KF (0.12
g, 2.1 mmol). After the mixture was stirred at 25 °C for 20 h,
workup and purification of the residue by column chromatog-
raphy (silica gel; hexane) afforded 0.097 g (90%) of 4-methyl-
biphenyl. Reactions carried out at 70 °C (1 h) afforded 0.104 g
(96%). The formation of 4-methylbiphenyl was confirmed by
1H and 13C NMR spectroscopy.23
Syn th esis of 2,6-Dim eth yl-4′-a cetylbip h en yl. Meth od
A: The general procedure was followed with 4-bromoacetophe-
none (0.13 g, 0.65 mmol), 2,6-dimethylphenylboronic acid
(0.106 g, 0.710 mmol), and KF (0.12 g, 2.1 mmol). After the
mixture was stirred at 70 °C for 8 h, workup and purification
of the residue by column chromatography (silica gel; 5% ethyl
acetate in hexane) afforded 0.133 g (91%) of 2,6-dimethyl-4′-
acetylbiphenyl. The formation of 2,6-dimethyl-4′-acetylbiphen-
1
yl was confirmed by H and 13C NMR spectroscopy.6c
Syn th esis of 4-P h en ylben zop h en on e. Meth od B: The
general procedure was followed with 4-chlorobenzophenone
(0.14 g, 0.65 mmol), phenylboronic acid (0.086 g, 0.71 mmol),
and KF (0.12 g, 2.1 mmol). After the mixture was stirred at
90 °C for 30 h, workup and purification of the residue by
column chromatography (silica gel; 10% ethyl acetate in
hexane) afforded 0.160 g (95%) of 4-phenylbenzophenone. The
identity of the product was confirmed by comparison of the
1H and 13C NMR spectra with an authentic sample (Aldrich).
Syn th esis of 2′-Meth yl-4-a cetylbip h en yl. Meth od B:
The general procedure was followed with 4-chloroacetophenone
(0.100 g, 0.65 mmol), o-tolylboronic acid (0.097 g, 0.71 mmol),
and KF (0.12 g, 2.1 mmol). After the mixture was stirred at
90 °C for 30 h, workup and purification of the residue by
column chromatography (silica gel; 10% ethyl acetate in
hexane) afforded 0.126 g (92%) of 2′-methyl-4-acetylbiphenyl.
The formation of 2′-methyl-4-acetylbiphenyl was confirmed by
1H and 13C NMR spectroscopy.5
Syn th esis of 4-P h en yla n isole. Meth od A: The general
procedure was followed with 4-bromoanisole (80.3 µL, 0.64
mmol), phenylboronic acid (0.086 g, 0.71 mmol), and KF (0.12
g, 2.1 mmol). After the mixture was stirred at 25 °C for 30 h,
workup and purification of the residue by column chromatog-
raphy (silica gel; 15% ethyl acetate/hexane) afforded 0.11 g
(93%) of 4-phenylanisole. Reactions carried out at 70 °C (1 h)
yielded 0.11 g (93%). The formation of 4-phenylanisole was
1
confirmed by H and 13C NMR spectroscopy.23
Syn th esis of 4-Acetylbip h en yl. Meth od A: The general
procedure was followed with 4-bromoacetophenone (0.127 g,
0.65 mmol), phenylboronic acid (0.086 g, 0.71 mmol), and KF
(0.12 g, 2.1 mmol). After the mixture was stirred at 25 °C for
20 h, workup and purification of the residue by column
chromatography (silica gel; 5% ethyl acetate/hexane) afforded
0.118 g (94%) of 4-acetylbiphenyl. Reactions carried out at 70
°C (1 h) yielded 0.120 g (96%). Meth od B: The general
procedure was followed with 4-chloroacetophenone (0.099 g,
0.64 mmol), phenylboronic acid (0.086 g, 0.71 mmol), and KF
(0.12 g, 2.1 mmol). After the mixture was stirred at 90 °C for
30 h, workup and purification by column chromatography
(silica gel; 5% ethyl acetate/hexane) afforded 0.113 g (90%).
The formation of 4-acetylbiphenyl was confirmed by 1H and
13C NMR spectroscopy.24
Syn th esis of 4-P h en ylben zon itr ile. Meth od B: The
general procedure was followed with 4-chlorobenzonitrile
(0.091 g, 0.66 mmol), phenylboronic acid (0.086 g, 0.71 mmol),
and KF (0.12 g, 2.1 mmol). After the mixture was stirred at
90 °C for 30 h, workup and purification of the residue by
column chromatography (silica gel; 5% ethyl acetate/hexane)
afforded 0.105 g (89%) of 4-phenylbenzonitrile. The formation
of 4-phenylbenzonitrile was confirmed by 1H and 13C NMR
spectroscopy.6c
Syn t h esis of 2′-Met h yl-4-cya n ob ip h en yl. Met h od A:
The general procedure was followed with 4-bromobenzonitrile
(0.12 g, 0.66 mmol), o-tolylboronic acid (0.097 g, 0.71 mmol),
and KF (0.12 g, 2.1 mmol). After the mixtue was stirred at 25
°C for 20 h, workup and purification of the residue by column
chromatography (silica gel; 15% ethyl acetate in hexane)
afforded 0.112 g (88%) of 2′-methyl-4-cyanobiphenyl. Reactions
carried out at 70 °C afforded 0.118 g (93%). Meth od B: The
general procedure was followed with 4-chlorobenzonitrile
(0.088 g, 0.64 mmol), o-tolylboronic acid (0.097 g, 0.71 mmol),
and KF (0.12 g, 2.1 mmol). After the mixture was stirred at
90 °C for 30 h, workup and purification of the residue by
column chromatography (silica gel; 15% ethyl acetate in
hexane) afforded 0.117 g (92%). The formation of the title
1
compound was confirmed by H and 13C NMR spectroscopy.3f
Syn th esis of 2′-Meth yl-4-ben zoylbip h en yl. Meth od B:
The general procedure was followed with 4-chlorobenzophe-
none, (0.14 g, 0.65 mmol), o-tolylboronic acid (0.097 g, 0.71
mmol), and KF (0.12 g, 2.1 mmol). After the mixture was
stirred at 90 °C for 30 h, workup and purification of the residue
by column chromatography (silica gel; 15% ethyl acetate in
hexane) afforded 0.159 g (90%) of 2′-methyl-4-benzoylbiphenyl.
The formation of 2′-methyl-4-benzoylbiphenyl was confirmed
by H and 13C NMR spectroscopy.3f
Loa d in g Exp er im en ts. Method A was followed with
4-bromoacetophenone (0.127 g, 0.64 mmol), phenylboronic acid
(0.086 g, 0.71 mmol), and KF (0.12 g, 2.1 mmol). The appropri-
ate amounts of Pd2(dba)3 and 1 were added by syringe
(solutions were prepared by successive dilution of 0.67 mM
THF solutions). After the mixture was stirred at 70 °C for 1
h, workup and purification of the residue by column chroma-
tography (silica gel; 15% ethyl acetate in hexane) afforded
4-acetylbiphenyl.
Disp la cem en t of 1 fr om 3 by Nitr ogen -Con ta in in g
Lew is Ba ses. An NMR tube was charged with (CH3CN)2PdCl2
(0.25 mL of a stock CDCl3 solution; 0.046 M) and 1 (0.25 mL
of a stock CDCl3 solution (0.092 M) also containing P(O)Ph3
as an internal standard; 0.092 M). A 31P{1H} NMR spectrum
was recorded confirming formation of 3.26 The Lewis base was
added and the tube shaken for 2 min. A 31P{1H} NMR
spectrum from an inverse gaited decoupling pulse program
Syn th esis of 2,4′-Dim eth ylbip h en yl. Meth od A: The
general procedure was followed with 4-bromotoluene (0.109
g, 0.64 mmol), o-tolylboronic acid (0.097 g, 0.71 mmol), and
KF (0.12 g, 2.1 mmol). After the mixture was stirred at 25 °C
for 17 h, workup and purification of the residue by column
chromatography (silica gel; hexane) afforded 0.10 g (86%) of
2,4′-dimethylbiphenyl. Reactions carried out at 70 °C (1 h)
afforded 0.11 g (95%). The formation of 2,4′-dimethylbiphenyl
1
was confirmed by H and 13C NMR spectroscopy.5
Syn th esis of 2,4,6-Tr im eth ylbip h en yl. Meth od A: The
general procedure was followed with 2- bromomesitylene (0.13
g, 0.65 mmol), phenylboronic acid (0.086 g, 0.71 mmol), and
KF (0.12 g, 2.1 mmol). Analysis of the reaction mixture after
24 h by GC revealed 50% conversion. Reactions carried out at
70 °C (8 h) afforded 0.11 g (87%) of 2,4,6-trimethylbiphenyl
after workup and purification by column chromatography
(silica gel; hexane). The formation of 2,4,6-trimethylbiphenyl
1
was confirmed by H and 13C NMR spectroscopy.25
(23) Old. D. W.; Wolfe, J . P.; Buchwald, S. L. J . Am. Chem. Soc.
1998, 120, 9722.
(24) Barba, I.; Chinchilla, R.; Gomez, C. Tetrahedron 1990, 46, 7813.
(25) Anderson, J . C.; Namli, H.; Roberts, C. A. Tetrahedron 1997,
53, 15123.
(26) Due to the low solubility of 3, the preparation of this complex
in situ afforded consistent results.

528 Organometallics, Vol. 22, No. 3, 2003
Pramick et al.
with a recycle delay of 30 s was recorded and the signals for
free 1 (δ -16.7 ppm) were integrated vs P(O)Ph3 to provide
the percent displacement of 1.
to M.T.B. Thanks are given to Dr. J anet Braddock-
Wilking for helpful discussions concerning quantitative
31P NMR spectroscopy.
Ack n ow led gm en t. This work was supported by a
New Faculty Award from the Henry and Camille
Dreyfus Foundation (Award-SU-00-020), the NSF-REU
program (CHE-9820553 to S.M.R. and S.M.B.), and a
Bucknell Undergraduate Research Program Fellowship
Su p p or tin g In for m a tion Ava ila ble: Molecular structure
information for 1. This material is available free of charge via
the Internet at http://pubs.acs.org.
OM020885I